Molecular, Macromolecular, and Supramolecular Glucuronide Prodrugs: Lead Identified for Anticancer Prodrug Monotherapy

Abstract

In this work, a tumor growth intervention by localized drug synthesis within the tumor volume, using the enzymatic repertoire of the tumor itself, is presented. Towards the overall success, molecular, macromolecular, and supramolecular glucuronide prodrugs were designed for a highly potent toxin, monomethyl auristatin E (MMAE). The lead candidate exhibited a fold difference in toxicity between the prodrug and the drug of 175, had an engineered mechanism to enhance the deliverable payload to tumours, and contained a highly potent toxin such that bioconversion of only a few prodrug molecules created a concentration of MMAE sufficient enough for efficient suppression of tumor growth. Each of these points is highly significant and together afford a safe, selective anticancer measure, making tumor‐targeted glucuronides attractive for translational medicine.

Per‐glycosylation of the Surface‐Accessible Lysines: One‐Pot Aqueous Route to Stabilized Proteins with Native Activity

“…We were specifically interested in the latter because small molecule glucuronides are highly polar and water-soluble. [25,26] We envisioned that glucuronidation can confer these properties to the protein molecules, which can result in a suit of beneficial properties. However, enzymatic glucuronidation (phase II natural metabolic reaction) is applied by Nature exclusively to small molecules, and proteins are not featured in the substrate scope of glucuronyl transferase.…”